Nanotechnology is a technique for controlling or manipulating materials at the atomic or molecular level, where various technologies are merged and is suitable for fabricating new materials and devices. The nanotechnology has wide application, such as electronics, materials, communications, machines, medicals, agricultures, energies, and environments. What makes the nano-scale particles important is that they provide unique features which micron-scale particles do not have. In particular, through controlling at nano-level, nano-scale particles may have outstanding improved materials properties, when compared to micron-scale particles.
Nano-scale magnetic materials are expected to be applied to various biomedical fields and contribute much to the growth of the fields. Magnetic nanoparticles are much smaller as compared to blood vessels and cells and are similar in size to proteins, which affords their accessibility to various types of biological tissues, and thus the magnetic nanoparticles have been used for biological diagnosis for several years. In addition, the rapid development of the nanotechnology in recent years allows manufacture of highly functional magnetic nanoparticles that can be under artificial magnetism control. At the same time, the chemical/biological stability in vivo thereof has been studied extensively.
Magnetic nanoparticles may be used in a wide variety of nano-bio technology such as molecular imaging using magnetic resonance imaging (MRI), tracking and diagnosis of diseases, hyperthermia, drugs delivery, magnetic-bio sensors, and microfluidic systems. In particular, magnetic nanoparticles can be used as a diagnostic probe for MRI. Under an external magnetic field, a magnetic moment of μ is induced in the nanoparticle. The induction field influences the spin-spin (T2) relaxation time and the spin-lattice (T1) relaxation time of the hydrogen atoms of water molecules surrounding the magnetic nanoparticles, thereby resulting in magnetic resonance signal enhancement. The imaging signal enhancement can be measured as relaxivity (R=1/T).
The above properties of the magnetic nanoparticles can be used for imaging the density of water proton in the tissue, the distribution of the blood vessel, diagnosis of diseases such as cancers, and the life phenomenon in a level of molecules and cells. Until now, the magnetic nanoparticle MRI contrast agent has been developed as follows:
U.S. Pat. No. 4,849,210 discloses 30 nm sized superparamagnetic magnetite particles that are incorporated into the biodegradable matrix material (proteins, carbohydrates, lipid, etc.) and their utilization in MRI of internal organs such as liver or spleen;
U.S. Pat. No. 5,023,072 discloses iron oxide superparamagnetic nanoparticles for MRI of the gastrointestinal tract. The paramagnetic, superparamagnetic and ferromagnetic particles, in combination with polysaccharide, are used for imaging of the gastrointestinal tract;
U.S. Pat. No. 5,055,288 discloses a biodegradable superparamagnetic iron oxide for vascular imaging. Individual iron oxide has a diameter of less than 50 nm and their aggregates have a diameter of less than 400 nm. Both are stable in a biological environment;
EP No. 0656368 discloses magnetic iron oxide nanoparticles that are coated with nano-sized carboxypolysaccharides. The nanoparticles are prepared by using a coprecipitation method, having a size in the range of about 2 to 7 nm, and are applied to systems such as cardiovascular system imaging and drug deliveries;
U.S. Pat. No. 6,203,777 discloses magnetite particles that are conjugated with carbohydrate. The nanoparticles are synthesized in aqueous media by using a coprecipitation method and conjugated with the carbohydrate polymers by using an ultrasonic wave reaction to be used as an MRI contrast agent for parenteral administration;
U.S. Pat. No. 6,599,498 discloses an MRI contrast agent that is coated with reduced carbohydrates and is stable against heating. The iron oxide nanoparticles are synthesized by using a coprecipitation method so as to have a size of about 10 nm, and applied to MRI for vascular systems;
US Pat. Application Publication No. US2006-0222594 discloses a magnetic nanoparticle MRI contrast agent which is capable of selective targeting, wherein iron oxide nanoparticles synthesized by a coprecipitation method are coated with micelles consisting of polymers;
Korean Patent Application Publication No. KR2006-0098213 discloses nanoparticles that are used for tumor diagnosis. The iron oxide magnetic nanoparticles that are synthesized by using high temperature thermal decomposition in an organic solvent are dissolved in water and attached to the antibody, to form a nanohybrid for tumor diagnosis.
The magnetic nanoparticles used for these MR contrast agents should fulfill the following requirements for their high performance MRI applications:
1) They should have a high magnetic moment enough to sensitively react to the external magnetic field;
2) They should exhibit excellent MR contrast effects;
3) They should be stably dispersed both in aqueous media and in vivo environments.
4) It should be feasible to conjugate them with biologically active materials; and
5) They should exhibit low toxicity and high biocompatibility.
The nanoparticle based imaging contrast agent prepared following the above-mentioned prior arts, commercially available contrast agents such as Feridex and Resovist, and iron oxide nanoparticles surrounded by water-soluble ligands have relatively low magnetic moment and poor MR contrast effect (R2). This leads to exhibit a reduced signal enhancement in MRI, and thus it has been pointed out that they have significant problems in the MRI diagnosis.
The way to resolve these problems is developing MR contrast agents comprising magnetic nanoparticles with enhanced magnetic moment. To achieve the purpose of increasing the magnetic moment, controlling the composition of metal oxide nanoparticles can be one method (Ittrich et al, Rofo 2005, 177, 1151; Shultz et al, J. Magn. Magn, Mater. 2007, 311, 464). It has been tried adding various metal dopants to iron oxide nanoparticle matrix. However, most of possible metallic dopants (e.g. Co, Ni, Mg, Ba, etc) do not increase magnetic moment and, in some cases, even reduce it after the addition (e.g. Co, Ni, Mg, Ba) (Valdés-Solís et al, Nanotechnology 2007, 18, 145603).
Recently, as an only one example of increasing the MRI contrast effects, Korean Patent Application Publication No. KR2006-0098213 discloses manganese-containing metal oxide nanoparticles with improved MR contrast effect. It is based on the improved magnetic moment due to the manganese. In this case, the inclusion of manganese increases magnetic moment of metal oxide by about 10%, but MR contrast effect (R2) resulted in 70˜100% increase.
Therefore, it is evident that development of a new metal oxide having more improved magnetic moment is very important in maximizing the MR contrast effect.